In studies related to the pain-producing mechanism, a receptor (TRPV1) for capsaicin, which is a main pungent taste component of chili pepper, was cloned in 1997 (Non-Patent Document 1). The TRPV1, which is a receptor that recognizes capsaicin, is widely expressed in primary sensory neurons involved in pain sensation, as well as in afferent sensory fibers including C fiber nerve endings, and many TRP family members have subsequently been cloned.
Members of the TRP family are structurally similar, having 6 transmembrane domains, and the N-terminal and C-terminal ends are located within the cell. TRPV1 allows cations such as a calcium ion and a sodium ion to flow into a cell when stimulated by capsaicin or by acid (pH 6.0 or less), heat (43° C. or more) or high osmotic pressure. Accordingly,
considering the expression sites of the TRPV1 receptor and the action of capsaicin, a marked contribution of the TRPV1 receptor to the excitement of nerve was assumed. Furthermore, contributions of TRPV1 in the living body have also been clarified in many existing reports, and in particular the involvement of TRPV1 in pain is suggested by the fact that thermal hypersensitivity due to neuropathic pain does not occur in mice in which TRPV1 is deleted (TRPV1 knockout mice), the fact that edema is suppressed in a Complete Freund's Adjuvant (CFA)-induce inflammatory pain model (Non-Patent Document 2), and the fact that the desensitization action of a previously reported TRPV1 agonist produced an analgesic effect in a neuropathic pain model and an inflammatory pain model (Non-Patent Document 3).
Called a capsaicin receptor, TRPV1 is a known target of therapies for treating pain, especially acute pain, chronic pain, neuropathic pain and visceral pain. TRPV1 is stimulated in particular by vanilloids such as capsaicin and by heat, protons and high osmotic pressure, and plays a central role in pain generation. It is also important in numerous other physiological and pathophysiological processes, and has been a target of many studies seeking therapies to treat diseases or disorders such as migraine, depression, neurodegenerative disease, cognitive disorders, anxiety, epilepsy, cough, diarrhea, pruritus, ocular pain, inflammation, cardiovascular system disorders, eating disorders, medication dependence, medication misuse and urinary incontinence and the like for example.
According to Example 71 of WO 2007/010383 (Patent Document 1), a compound (1) having excellent TRPV1 antagonism was obtained as a solid.